This invention was made in part with government funding and the government has certain rights in the invention.
This invention relates to the use of recombinant DNA techniques to make analogs of toxin molecules, and to the use of such molecules to treat medical disorders.
The literature contains a number of examples of hybrid molecules containing a specific binding ligand-portion and a toxin portion (e.g., ricin or diphtheria toxin); the ligand targets the toxin to an unwanted class of cells, sparing healthy cells, to which the ligand fails to bind.
For example, Bacha et al. U.S. Pat. No. 4,468,382 (hereby incorporated by reference) describes hybrid molecules made by derivatizing a neuropeptide hormone (e.g., thyrotropin releasing hormone) and an enzymically active fragment of diphtheria toxin using sulfur-containing groups and then reacting the derivatized molecules to join them via a disulfide bond. One disadvantage of this approach is that the site of derivatization on both molecules cannot be precisely controlled, so that the final product is heterogeneous, containing some molecules in which derivatization and coupling has impaired the toxicity or binding capacity of the hybrid molecule.
An approach which deals with this problem of heterogenicity is described in Murphy PCT International Publication No. WO/83/0397l (hereby incorporated by reference). The Murphy application describes hybrid proteins encoded by genes encoding both the toxin and the specific binding portion of the hybrid protein. This approach, of course, can be used only for DNA-encoded peptide ligands.